Estrogen is protective against tissue damage and neurological deficit after experimental cerebral ischemia. Although the precise mechanisms are unknown, estrogen's beneficial properties are in part linked to rapid activation of signal transduction pathways that lead to the transcription of neuroprotective genes. Signal transducer and activator of transcription 3 (STATS) is a transcription factor that is activated in response to both estrogen and ischemia, and is known to bind and stimulate the transcription of neuroprotective genes, such as bcl-2 and bcl-xL. We propose to test the overall hypothesis that estrogen's neuroprotective effects in cerebral ischemia are mediated, in part, via STATS. We will inhibit STATS activation to determine its role in mediating the effect of estradiol to reduce infarct size after middle cerebral artery occlusion (MCAO) in ovariectomized female rats. We will use Western blotting to determine the effect of estradiol on STATS phosphorylation and nuclear translocation. Finally, we will use quantitative real-time PCR and electrophoretic mobility shift assay (EMSA) to determine the effect of estradiol on bcl-2 and bcl-xL gene expression and potential STAT-3 binding to their respective promoters in brain after MCAO. [unreadable] [unreadable]